Recently, our appreciation of the role of Fcgamma receptors in immunobiology has expanded substantially. The recognition that there are also non-Ig ligands for FcgammaR and that there are multiple functions for the Fcgamma underscores a role for these receptors in immune system homeostasis and in modulation of the antigen-driven immune repertoire, as well as in efferent inflammatory cell programs. Three observations highlights this perspective: First, FcgammaRIa and FcgammaRIIa are recognized as the human receptors for CRP, a critical opsonin for the innate immune system. Second, the presentation of antigen in the context of antibody amplifies the host immune response by >100=fold, a response abrogated in FcgammaRI and FcgammaRIII knock-out mice. Third, FcgammaRIa preferentially stimulates IL-10 production and down regulates inflammation compared the other "activating" receptor in mouse, FcgammaRIIIa although both receptors use the same gamma-chain for their tyrosine (ITAM)-based signaling. Additional observations provide further indications that important biological properties are not captured by the dichotomous "activating and inhibitory" receptor framework: First, the role(s) of the alpha-chain cytoplasmic (CY) domain has now been established for cytokine production. Second, the observations that the alpha CY domain modulates both tyrosine phosphorylation (pY) and antigen presentation suggests a basis for the special role of the FcgammaRI in response and response amplification to antigen. Our data now indicate a novel and unanticipated role in function for the unique CY domains of the ligand-binding alpha-chains which lack pY signaling motifs. Accordingly, the specific aims of this proposal are: to define the unique alpha-chain CY domain binding partners for the gamma-chain-associated FcgammaRia and to define their contributions to early signaling events, to gene transcription and to antigen presentation. to define the unique alpha-chain CY domain binding partners of other gamma-chain-associated receptors (FcgammaRIIIa, FcalphaRia, ILT/LIR) and, through analysis of a series of alpha-chain CY chimeras, to characterize the unique contributions of each alpha-chain CY domain; to identify unique human alpha-chain CY domain allelic variants for the gamma-chain associated receptors, to determine their functional characteristics and to establish their association with altered host defense and immune disease (e.g., RA, SLE, IgA nephropathy). Understanding the unique properties of the CY will enable such unique properties to be harnessed to therapeutic advantage.